The long-term goal of this proposal is to develop novel nanoparticles, "platelet-mimicking nanoparticles," as a drug carrier that can target and deliver a therapeutic agent to the injured vessel wall after cardiovascular interventions such as angioplasty. Our strategy is to mimic the binding of the glycoprotein Ib (GPIb) of platelets (a blood cell type) through either P-selectin expressed in damaged endothelial cells (ECs) or vWF deposited on injured subendothelium, which is critical for the initial interaction of circulating platelets onto the injured vessel wall under high shear conditions. The major advantage of using GPIb-nanoparticles for targeting drug delivery in our proposal, compared to current targeting strategies including anti-P-selectin antibodies, is that GPIb specially binds to both P- selectin expressed on damaged ECs and vWF deposited on injured subendothelium, thereby accumulating more nanoparticles as drug carriers to the injured wall site for effective drug delivery. To accomplish our goal, three specific aims are: (1) Develop drug (dexamethasone)-loaded biodegradable GPIb-nanoparticles using a standard double emulsion method. (2) Investigate the targeting activity and effectiveness of these nanoparticles in vitro using the parallel flow plate system, surfaces coated with P-selectin or vWF, and activated ECs. (3) Evaluate the efficacy of our novel platelet-mimicking nanoparticles in vivo using rat balloon injury models. The assessed parameters for these specific aims include the binding sites and stability of GPIb, changes in nanoparticle properties, the adhesion and uptake of GPIb-nanoparticles in activated endothelial cells under flow conditions as well as pharmacological activities of these nanoparticles in inflamed ECs and injured rat arteries. Cardiovascular interventions often injure the vessel wall, leading to the development of late pathological conditions such as inflammation and restenosis. The development of our novel platelet- mimicking nanoparticles is a unique strategy to rapidly target and deliver therapeutic agents to damaged ECs and subendothelium, despite the shear influence, for more effective therapies to treat these complications. Project Narrative Cardiovascular interventions such as angioplasty and stenting, used to open an area of blockage inside the diseased, narrowed blood vessel, often injure the vessel wall, leading to the development of late pathological conditions such as inflammation and restenosis (re-narrowing of an artery). This research project is to develop novel nanoparticles that mimic the adhesive properties of platelets, a blood cell type, bound to the injured vessel wall for targeting drug delivery. Our platelet- mimicking nanoparticles will rapidly target and deliver drugs only to the damaged vessel wall for an effective treatment, leading to the reduction of the artery's re-narrowing after cardiovascular interventions.